Arylcyclopropylcarboxylic amides as potassium channel openers

ABSTRACT

The present invention provides novel arylcyclopropylcarboxylic amides and related derivatives having the general Formula I 
                         
wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined in the specification, or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof which are openers or activators of KCNQ potassium channels. The present invention also provides pharmaceutical compositions comprising said arylcyclopropylcarboxylic amides and to the method of treatment of disorders sensitive to KCNQ potassium channel opening activity such as migraine or a migraine attack, bipolar disorders, epilepsy, acute and chronic pain and anxiety.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a non-provisional application which claims the benefit of U.S.Provisional Application No. 60/428,337 filed Nov. 22, 2002.

FIELD OF THE INVENTION

The present invention is directed to novel arylcyclopropylcarboxylicamide derivatives which are modulators of KCNQ potassium channels andare therefore useful in treating disorders responsive to the modulationof the potassium channels. The present invention also provides a methodof treatment with the novel arylcyclopropylcarboxylic amide derivativesand to pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

Potassium (K⁺) channels are considered to be the most diverse class ofion channels and have several critical roles in cell function. This hasbeen demonstrated in neurons where K⁺ channels are responsible, in part,for determining cell excitability by contributing to membranerepolarization following depolarization, resting membrane potential, andregulation of neurotransmitter release. The M-current has long beendescribed, by electrophysiology recording methods and by pharmacology,as a dominant conductance in controlling neuronal excitability.Pharmacological activation or suppression of M-currents by smallmolecules could have profound effects in controlling neuronalexcitability. Recently, Wang et al., Science, 282:1890–1893, (1998)reported that co-assembly of the KCNQ2 and KCNQ3 potassium channelsunderlies the native M-current in neurons.

Activation or opening of the KCNQ channel(s), particularly the KCNQ2 orKCNQ2/3 channel(s), mutated or wild type, may prove to be beneficial inincreasing hyperpolarization of neurons, thereby resulting in protectionfrom abnormal synchronous firing during a migraine attack. The presentinvention provides a solution to the problem of abnormal synchronousfiring of neurons related to migraine headache by demonstrating thatmodulators, preferably openers, of KCNQ potassium channels increaseshyperpolarization of neurons which protects against abnormal synchronousneuron firing involved in migraine attacks.

Although the symptom pattern varies among migraine sufferers, theseverity of migraine pain justifies a need for vigorous, yet safe andeffective, treatments and therapies for the great majority of cases.Needed in the art are agents that can be used to combat and relievemigraine (and diseases similar to and mechanistically related tomigraine), and even prevent the recurrence of migraine. Also needed areanti-migraine agents which are effective in the treatment of acutemigraine, as well as in the prodrome phase of a migraine attack. Thus, aclear goal in the art is to discover new, safe, nontoxic and effectiveanti-migraine compounds for use as drugs, and in anti-migrainecompositions and treatments.

Because migraine afflicts a large percentage of the population, there isa need to discover compounds and agents that are useful in therapeuticsand treatments, and as components of pharmaceutical compositions, forreducing, ameliorating, or alleviating the pain and discomfort ofmigraine headache and other symptoms of migraine. The present inventionsatisfies such a need by providing compounds that function as openers ofthe KCNQ family of potassium channel proteins to serve as anti-migraineagents or drugs and to comprise compositions to treat migraine, asdescribed herein.

A broad range of cinnamide compounds are known and new compoundscontinue to be reported with a broad range of utility. Some of thesecompounds can be found in the disclosures of WO 00/07993 published Feb.17, 2000, EP 810220A1, published Dec. 3, 1997, U.S. Pat. No. 4,927,838issued May 22, 1990 to Guthrie, et al., U.S. Pat. No. 6,046,239 issuedApr. 4, 2000 to Lennox, et al., WO 00.42013, published Jul. 20, 2000, WO01/10381 published Feb. 15, 2001, WO 01/10380 published Feb. 15, 2001,JP45-14291 published May 21, 1970, and JP2-138159 published May 28,1990. The compounds described in these patents are distinct from thoseof the present invention.

SUMMARY OF THE INVENTION

The present invention provides novel arylcyclopropylcarboxylic amidesand related derivatives having the general Formula I

wherein R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined below, or anontoxic pharmaceutically acceptable salt, solvate or hydrate thereofwhich are openers or activators of KCNQ potassium channels. The presentinvention also provides pharmaceutical compositions comprising saidarylcyclopropylcarboxylic amides and to the method of treatment ofdisorders sensitive to KCNQ potassium channel opening activity such asmigraine or a migraine attack, bipolar disorders, epilepsy, acute andchronic pain and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel arylcyclopropylcarboxylic amidesand related derivatives which are modulators of the KCNQ potassiumchannels and which have the general Formula I or a pharmaceuticallyacceptable salt thereof

wherein R is C₁₋₄ alkyl, CF₃ or hydroxymethyl; R¹ and R² are eachindependently hydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ isselected from the group consisting of optionally substitutedmorpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, inwhich said substituent is independently selected from the groupconsisting of C₁₋₄alkyl, dimethylamino, hydroxymethyl, chloro andfluoro; R⁵is hydrogen or fluoro; or R⁴ and R⁵ taken together are—CH═CH—CH═CH— or —CH₂CH₂O—; and R³, R⁶ and R⁷ are each independentlyselected from hydrogen or fluoro, which are openers of the KCNQpotassium channels and are useful in the treatment of disorders whichare responsive to the opening of the KCNQ potassium channels.

The present invention also provides a method for the treatment oralleviation of disorders associated with KCNQ potassium channelpolypeptides and, in particular, human KCNQ potassium channelpolypeptides in a mammal in need thereof which comprises administeringtogether with a conventional adjuvant, carrier or diluent atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. Preferably, the compounds ofFormula I are useful in the treatment of migraine or a migraine attack,cluster headaches, bipolar disorder, convulsions, mania, acute mania,epilepsy, anxiety, depression, schizophrenia, functional boweldisorders, stroke, traumatic brain injury, multiple sclerosis,neurodegenerative disorders or alleviating pain such as musculoskeletalpain, post operative pain, surgical pain, inflammatory pain, neuropathicpain such as diabetic neuropathy and pain associated with cancer andfibromyalgia.

The term “pain” as used herein and in the claims means all types ofacute and chronic pain, such as neuropathic pain, post-operative pain,chronic lower back pain, cluster headaches, herpes neuralgia, phantomlimb pain, central pain, dental pain, opioid-resistant pain, visceralpain, surgical pain, bone injury pain, pain during labor and delivery,pain resulting from burns, including sunburn, post partum pain,migraine, angina pain, and genitourinary tract-related pain includingcystitis and the term also is intended to include nociceptive pain ornociception.

The term “C₁₋₄ alkyl” as used herein and in the claims means straight orbranched chain alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, and tert-butyl. The term “C₁₋₄ alkoxy” as used hereinand in the claims means an oxygen substituted with straight or branchedchain alkyl groups and includes groups such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, and tert-butoxy. The term “halogen” asused herein and in the claims is intended to include bromine, chlorine,iodine and fluorine.

As the compounds of the present invention contain a substitutedcyclopropyl group as part of the structure, the compounds of theinvention exist in either of two geometric isomeric forms, namely as cisor trans isomers. Preferred are the trans isomers in which the arylgroup and the amide group, C(O)NH, are trans to each other. As thecompounds of the present invention possess an asymmetric carbon atom,such as the carbon adjacent to the amide nitrogen and to which thephenyl is attached, the present invention includes the racemate as wellas the individual enantiomeric forms of the compounds of Formula I asdescribed herein and in the claims. Preferred embodiments of compoundsof Formula I include the racemate, a single enantiomer, and in certaininstances a single enantiomer wherein the carbon adjacent to the amidenitrogen and to which the phenyl is attached has the (S)stereochemistry. Mixtures of isomers of the compounds of Formula I orchiral precursors thereof can be separated into individual isomersaccording to methods which are known per se, e.g. fractionalcrystallization, adsorption chromatography or other suitable separationprocesses. Resulting racemates can be separated into antipodes in theusual manner after introduction of suitable salt-forming groupings, e.g.by forming a mixture of diastereosiomeric salts with optically activesalt-forming agents, separating the mixture into diastereomeric saltsand converting the separated salts into the free compounds. Theenantiomeric forms may also be separated by fractionation through chiralhigh pressure liquid chromatography columns, according to proceduresdescribed herein.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms including hydrated forms suchas monohydrate, dihydrate, trihydrate, hemihydrate, tetrahydrate and thelike. The products may be true solvates, while in other cases, theproducts may merely retain adventitious solvent or be a mixture ofsolvate plus some adventitious solvent. It should be appreciated bythose skilled in the art that solvated forms are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

In the method of the present invention, the term “therapeuticallyeffective amount” means the total amount of each active component of themethod that is sufficient to show a meaningful patient benefit, i.e.,amelioration or healing of conditions which respond to modulation of theKCNQ potassium channels. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously. Theterm “KCNQ” as used herein and in the claims means the family of KCNQ2,KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides as well asheteromultimers of different individual family members which include butare not limited to KCNQ2/3, KCNQ2/5 and KCNQ3/5. The terms “treat,treating, treatment” as used herein and in the claims means preventing,alleviating or ameliorating diseases and/or symptoms associated withdysfunction of cellular membrane polarization and conductance of humanKCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides and, inparticular, migraine and/or symptoms that precede a full-blown migraineattack, neuropathic pain, mania and anxiety.

The general procedures used to synthesize intermediates and thecompounds of Formula I are described in Reaction Schemes 1–4 and areillustrated in the preparations and examples. Reasonable variations ofthe described procedures, which would be evident to one skilled in theart, are intended to be within the scope of the present invention.

Reaction Scheme 1 depicts the preparation of cyclopropanecarboxylic acidderivatives useful as intermediates in the synthesis of compounds ofFormula I. Step 1 of Reaction Scheme 1 depicts the reaction of anappropriate cinnamic acid of Formula II with O,N-dimethyl-hydroxylaminehydrochloride and triethylamine to furnish compound of Formula III.Compound of Formula III can be converted to compound of Formula IV bytreatment with trimethylsulfoxonium iodide and sodium hydride. Compoundof Formula IV can be hydrolyzed under basic conditions such as aqueoussodium hydroxide followed by acidification to give compound of FormulaV.

Reaction Scheme 2 depicts a general method useful for the preparation ofamines of Formula VIII which are useful intermediates for thepreparation of compounds of Formula I. Compound of Formula VI wasconverted to compound of Formula VII by reaction with hydroxylaminehydrochloride in the presence of a base such as triethylamine. Compoundof Formula VII underwent catalytic hydrogenation to give amine withFormula VIII.

Reaction Scheme 3 depicts an alternative method useful for thepreparation of amines of Formula VIII. Compound of Formula VI underwentreductive alkylation with ammonia and a reducing agent such as sodiumcyanoborohydride to give compound of Formula VIII.

Reaction Scheme 4 depicts the preparation of compounds of generalFormula I from the acid of general Formula V and amine of Formula VIII.Reaction Scheme 4 depicts the preparation of compounds of generalFormula I from the acid of general Formula V and amine of generalFormula VIII. The coupling of the acid, V, and amine, VIII is carriedout by methodology well known in the art for the conversion of an acidand an amine to form an amide. Useful reactive derivatives of the acidof Formula VIII include, but are not limited to, activated esters,reactive mixed anhydrides, and acid halides (such as the acid chloride,prepared e.g. with thionyl chloride or oxalyl chloride). A preferredmethod is to condense the acid of Formula V with the amine of FormulaIII in the presence of an appropriate condensing agent, for example,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) ordicyclohexylcarbodiimide (DCC), and a basic tertiary amine, such as4-dimethylaminopyridine (DMAP), in an inert solvent such asdichloromethane. The more preferred method is to couple the acid ofFormula V with the amine of Formula VIII in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (EDC) inthe presence of 4-dimethylaminopyridine (DMAP), triethylamine (Et₃N), indichloromethane.

In one embodiment, the present invention includes compounds of Formula Ior a pharmaceutically acceptable salt thereof

wherein R is C₁₋₄ alkyl, CF₃ or hydroxymethyl; R¹ and R² are eachindependently hydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ isselected from the group consisting of optionally substitutedmorpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, inwhich said substituent is independently selected from the groupconsisting of C₁₋₄alkyl, dimethylamino, hydroxymethyl, chloro andfluoro; R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together are—CH═CH—CH═CH— or —CH₂CH₂O—; and R³, R⁶ and R⁷ are each independentlyselected from hydrogen or fluoro.

In a preferred embodiment, the invention includes compounds of FormulaIa or a pharmaceutically acceptable salt thereof

wherein R is methyl; R¹ and R² are each independently hydrogen, C₁₋₄alkyl, halogen or morpholin-4-yl; R⁴ is selected from the groupconsisting of optionally substituted morpholin-4-yl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent isindependently selected from the group consisting of C₁₋₄alkyl,dimethylamino, hydroxymethyl, chloro and fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; andR³, R⁶ and R⁷ are each independently selected from hydrogen or fluoro.

In a preferred embodiment, the invention includes compounds of FormulaIb or a pharmaceutically acceptable salt thereof

wherein R is hydroxymethyl; R¹ and R² are each independently hydrogen,C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ is selected from the groupconsisting of optionally substituted morpholin-4-yl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent isindependently selected from the group consisting of C₁₋₄alkyl,dimethylamino, hydroxymethyl, chloro and fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; andR³, R⁶ and R⁷ are each independently selected from hydrogen or fluoro.

Preferred compounds for use in the method of the present inventioninclude the compounds of Formula I listed below:

-   2-(2-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;-   2-(3-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;-   2-(4-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;-   2-(2-fluoro-phenyl)-cyclopropanecarboxylic    acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;-   2-(3-fluoro-phenyl)-cyclopropanecarboxylic    acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;-   2-(4-fluoro-phenyl)-cyclopropanecarboxylic    acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;-   2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic    acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;-   2-(2-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;-   2-(3-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;-   2-(4-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;-   2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic    acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;-   2-(4-fluoro-phenyl)-cyclopropanecarboxylic    acid(1-naphthalen-2-yl-ethyl)-amide;-   2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic    acid(1-naphthalen-2-yl-ethyl)-amide;-   2-(4-fluoro-phenyl)-cyclopropanecarboxylic    acid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyll}-amide;-   2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic    acid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-amide;-   2-(3-fluoro-phenyl)-cyclopropanecarboxylic    acid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;-   2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic    acid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;-   (S)-2-phenyl-cyclopropanecarboxylic    acid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;-   (S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylic    acid{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide;-   (S)-2-phenyl-cyclopropanecarboxylic    acid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; and-   (S)-2-(2-fluoro-phenyl)-cyclopropanecarboxylic    acid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide;-   or a pharmaceutically acceptable salt thereof.

BIOLOGICAL ACTIVITY

KCNQ Patch-Clamp Methods and Results

Potassium (K⁺) channels are structurally and functionally diversefamilies of K⁺-selective channel proteins which are ubiquitous in cells,indicating their central importance in regulating a number of key cellfunctions [Rudy, B., Neuroscience, 25: 729–749 (1988)]. While widelydistributed as a class, K⁺ channels are differentially distributed asindividual members of this class or as families. [Gehlert, D. R., etal., Neuroscience, 52: 191–205 (1993)]. In general, activation of K⁺channels in cells, and particularly in excitable cells such as neuronsand muscle cells, leads to hyperpolarization of the cell membrane, or inthe case of depolarized cells, to repolarization. In addition to actingas an endogenous membrane voltage clamp, K⁺ channels can respond toimportant cellular events such as changes in the intracellularconcentration of ATP or the intracellular concentration of calcium(Ca²⁺). The central role of K⁺ channels in regulating numerous cellfunctions makes them particularly important targets for therapeuticdevelopment. [Cook, N. S., Potassium channels: Structure,classification, function and therapeutic potential. Ellis Horwood,Chinchester (1990)]. One class of K+ channels, the KCNQ familyexemplified by KCNQ2, KCNQ2/3 heteromultimers, and KCNQ5, is regulatedby transmembrane voltage and plays a potentially important role in theregulation of neuronal excitability [Biervert, C., et al., Science, 279:403–406 (1998); Lerche, C. et al., J. Biol. Chem. 275:22395–22400(2000); Wang, H. et al., Science, 282:1890–1893 (1998)].

An opener of KCNQ channels, such as the KCNQ2 and KCNQ2/3 channel openerretigabine, exerts its cellular effects by increasing the openprobability of these channels [Main J., Mol Pharmacol 58(2):253–62(2000); Wickenden, A. et al., Mol. Pharm. 58:591–600 (2000)]. Thisincrease in the opening of individual KCNQ channels collectively resultsin the hyperpolarization of cell membranes, particularly in depolarizedcells, produced by significant increases in whole-cell KCNQ-mediatedconductance.

Whole-cell patch-clamp recordings were made from an HEK 293 stable cellline expressing mKCNQ2 channels, maintained in culture for 1–2 days.Patch pipettes had initial resistances of 2.5–4 MΩ. Currents wererecorded with an EPC-9 amplifier (HEKA, Lambrecht, Germany) controlledwith software (Pulse, HEKA) run on a standard lab PC. Series resistancecompensation was used during current recording, and set at 80%. Theseries resistance (R) and cell capacitance (C) were determinedelectronically by subtracting the capacitive currents at the onset andoffset of a 5 mV voltage step. The cancellation of whole-cell capacitivetransients was virtually complete in all cells. Analog current signalswere low-pass filtered at 2.9 kHz using a four-pole Bessel filter −3 dB)and stored on a local network server computer at a sampling rate of 1.5kHz. All recordings were performed at room temperature (20–22° C.). Thepipette solution contained (mM): KCl, 150; CaCl₂, 2.5; EGTA, 5; MgCl₂,1; HEPES, 10; pH to 7.3 with KOH, and Osmolality of 290–300 mOsm. Theextracellular solution contained (mM): NaCl, 140; KCl, 2.5; CaCl₂, 2.5;MgCl₂, 1; glucose, 10; HEPES, 10; pH to 7.3 with NaOH, and Osmolality of305–310 mOsm

For analysis of agents effects on mKCNQ2 currents, the raw currentrecords were displayed on the digital oscilloscope of the Pulse softwareapplication. Concentration response data were generated by measuring thedifference in the steady-state amplitude of current in the presence ofcompound at the end of a 600 ms voltage-clamp step from a holdingpotential of −80 mV. The concentration-response data were fitted withHill-type equations:I=I _(max)/(1+EC ₅₀ /[A] ^(nH)),where I is the steady-state current at a given concentration of agonist[A]; and I_(max), EC₅₀ and nH are parameters estimated from the curvefit. In some cases the concentration-response data were fitted withequations consisting of the sum of two Hill-type components.Current-voltage (I/V) relationships for agonist-evoked currents wereobtained by performing 600 ms voltage steps (−110 mV to +40 mV) in theabsence and presence of agonist. The effect of a representative compoundof Formula I on KCNQ currents is listed in Table 1.

TABLE 1 Example No. EC₅₀ (μM) @ −40 mv) I_(max) (%) 13 0.597 1232Thallium Assay Methods and Results

A thallium flux assay was used to detect and characterize openers ofKCNQ potassium channels. The thallium assay is generally described inInternational application WO 02/31508 published Apr. 18, 2002. Morespecifically, the thallium influx assay to detect compounds that blockor open the voltage-gated K⁺ channel KCNQ2 is described in Example IV ofthe published WO 02/31508 application.

For data analysis, the amplitude of the average of the negative controlswas subtracted from all wells. The amplitudes of the test compounds werethen compared to the value of four standard deviations of the negativecontrol wells. The lowest concentration of a test compound sufficient togenerate a signal amplitude greater than or equal to four standarddeviations from the amplitude of the negative controls was defined asthe minimal active concentration.

For generating EC₅₀ values, compounds were serially diluted in 1:3volume increments to produce a 10 point concentration series. EC₅₀values were calculated by fitting the resulting amplitudes to asingle-site logistic equation. EC₅₀ was defined as the concentration oftest compound required to yield 50% of the maximal response. Maximalresponse (Maximal opening) was the largest signal amplitude above thenegative control generated by any concentration of a test compound.

The following Table 2 contains data which show that compounds of thepresent invention are openers of the KCNQ channels.

TABLE 2 Example No. EC₅₀ (μM)  9 0.022 11 1.44 13 0.012 14 0.001 150.001 32 0.001 34 2.21

In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical adjuvant, carrier or diluent.

In still another embodiment, this invention relates to a method oftreatment or prevention of disorders responsive to opening of KCNQpotassium channels in a mammal in need thereof, which comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I. Preferably, the compounds of Formula I are usefulin the treatment of treatment of migraine or a migraine attack, clusterheadaches, bipolar disorder, convulsions, mania, acute mania, epilepsy,anxiety, depression, schizophrenia, functional bowel disorders, stroke,traumatic brain injury, multiple sclerosis, neurodegenerative disordersor alleviating pain such as musculoskeletal pain, post operative pain,surgical pain, inflammatory pain, neuropathic pain such as diabeticneuropathy and pain associated with cancer and fibromyalgia.

For therapeutic use, the pharmacologically active compounds of Formula Iwill normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inassociation with a solid or liquid pharmaceutically acceptable carrierand, optionally, with pharmaceutically acceptable adjutants andexcipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral,parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, plated in a hard gelatincapsule in powder or pellet form, or in the form of a troche orlonzenge. The solid carrier may contain conventional excipients such asbinding agents, fillers, tableting lubricants, disintegrants, wettingagents and the like. The tablet may, if desired, be film coated byconventional techniques. If a liquid carrier is employed, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile vehicle for injection, an aqueous or non-aqueous liquidsuspension, or may be a dry product for reconstitution with water orother suitable vehicle before use. Liquid preparations may containconventional additives such as suspending agents, emulsifying agents,wetting agents, non-aqueous vehicle (including edible oils),preservatives, as well as flavoring and/or coloring agents. Forparenteral administration, a vehicle normally will comprise sterilewater, at least in large part, although saline solutions, glucosesolutions and like may be utilized. Injectable suspensions also may beused, in which case conventional suspending agents may be employed.Conventional preservatives, buffering agents and the like also may beadded to the parenteral dosage forms. Particularly useful is theadministration of a compound of Formula I directly in parenteralformulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula I according to the invention. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

The dosage of the compounds of Formula I to achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of potassiumchannel activating activity desired and the potency of the particularcompound being utilized for the particular disorder of diseaseconcerned. It is also contemplated that the treatment and dosage of theparticular compound may be administered in unit dosage form and that theunit dosage form would be adjusted accordingly by one skilled in the artto reflect the relative level of activity. The decision as to theparticular dosage to be employed (and the number of times to beadministered per day is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition as described herein is an amount of active ingredientfrom about 0.01 μg/kg to 10 mg/kg body weight. For parenteraladministration, the dose may be in the range of 0.1 μg/kg to 1 mg/kgbody weight for intravenous administration. For oral administration, thedose may be in the range about 0.1 μg/kg to 5 mg/kg body weight. Theactive ingredient will preferably be administered in equal doses fromone to four times a day. However, usually a small dosage isadministered, and the dosage is gradually increased until the optimaldosage for the host under treatment is determined.

However, it will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances including the condition to be treated, the choiceof compound of be administered, the chosen route of administration, theage, weight, and response of the individual patient, and the severity ofthe patient's symptoms.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way inasmuch as manyvariations of the invention are possible within the spirit of theinvention.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040–0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on a Bruker DRX-500f at 500 MHz; a Bruker DPX-300B at 300 MHz;or a Varian Gemini 300 at 300 MHz. The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30) and DMSO-d₆ (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in hertz. LC/MSwas performed on a Shimadzu LC-10AS liquid chromatograph using aSPD-10AV UV-VIS detector with Mass Spectrometry data determined using aMicromass LC Platform in positive electrospray ionization mode (ESI+).Mass Spectrometry (MS) data was obtained using a standard flow injectiontechnique on a Micromass LC Platform in positive electrospray ionizationmode (ESI+) unless otherwise noted. High resolution mass spectrometry(HRMS) data was obtained using a standard flow injection technique on aFinnigan MAT 900 mass spectrometer in electrospray ionization (ESI)mode. The analytical reverse phase HPLC method is as follows unlessotherwise noted: Column YMC ODS-A C18 S7 (3.0×50 mm), Start % B=0, Final% B=100, Gradient Time=2 min, Flow rate 5 ml/minutes. Wavelength=220 nm,Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH—10% H₂O-0.1%TFA; and R_(t) in min. Preparative reverse phase HPLC was performed on aShimadzu LC-8A automated preparative HPLC system with detector (SPD-10AVUV-VIS) wavelength and solvent systems (A and B) the same as aboveexcept where otherwise noted.

The following LCMS conditions were employed for the analysis of thecompounds of Examples 1–36 and are as follows:

-   a) YMC Xterra C18 S7 3.0×50 mm; 0–100% gradient over 2 min; 5 mL/min    flow rate-   b) Primeshere C18-HC 4.6×30 mm; (5 mM NH₄OAc) 0–100% gradient over 2    min; 4 mL/min flow rate-   c) Xterra C8-HC 4.6×30 mm; (0.05% TFA) 0–100% gradient over 2 min; 4    mL/min flow rate    SolventA=10% CH₃CN-90% H₂O-5 mM NH₄OAc    SolventB=90% CH₃CN-10% H₂O-5 mM NH₄Oac

PREPARATION OF INTERMEDIATES Preparation 1 Preparation of2-(2-chloro-phenyl)-cyclopropanecarboxylic acid

Step A: 3-(2-Chloro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 2-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g), DMAP (12.2g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂ (300 mL) wasstirred at room temperature for 16 h. The reaction was quenched withwater, and the organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrated was evaporated in vacuo, and the crude productwas purified by silica gel flash chromatography eluting with 33% hexanesin ethyl acetate gave the title compound (22 g) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 8.13 (d, J=15.8 Hz, 1H), 7.66–7.63 (m, 1H),7.41–7.38 (m, 1H), 7.28–7.25 (m, 1H), 7.04 (d, J=15.8 Hz, 1H), 3.75 (s,3H), 3.30 (s, 3H).

MS (M+H)⁺ 226.

Step B: 2-(2-Chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(2-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (22 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (17 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.37–7.34 (m, 1H), 7.20–7.15 (m, 1H),7.08–7.05 (m, 1H), 3.73 (s, 3H), 3.25 (s, 3H). 2.80–2.74 (m, 1H),2.35–2.29 (m, 1H), 1.67–1.60 (m, 1H), 1.37–1.31 (m, 1H).

MS (M+H)⁺ 240.

Step C: Preparation of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acid

A mixture of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.8 g).

¹H NMR (300 MHz, CDCl₃) δ 7.39–7.36 (m, 1H), 7.20–7.18 (m, 1H),7.00–7.01 (m, 1H), 2.85–2.80 (m, 1H), 1.84–1.80 (m, 1H), 1.73–1.66 (m,1H), 1.46–1.39 (m, 1H).

MS (M−H)⁺ 195.

Preparation 2 Preparation of 2-(3-chloro-phenyl)-cyclopropanecarboxylicacid

Step A: 3-(3-Chloro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 3-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g), DMAP (12.2g), triethylamine (28 mL), and NH(Me)OMe.HCl (12 g) in CH₂Cl₂ (300 mL)was stirred at room temperature for 16 h. The reaction was quenched withwater, and the organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrated was evaporated in vacuo, and the crude productwas purified by silica gel flash chromatography eluting with 33% hexanesin ethyl acetate gave the title compound (20 g) as a solid.

Step B: 2-(3-Chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(3-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (14 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.20–7.01 (m, 3H), 3.70 (s, 3H), 3.23 (s, 3H).2.48–2.43 (m, 2H), 1.67–1.60 (m, 1H), 1.32–1.25 (m, 1H).

MS (M+H)⁺ 240.

Step C: Preparation of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acid

A mixture of 2-(3-chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.4 g).

¹H NMR (300 MHz, CDCl₃) δ 7.28–7.18 (m, 1H), 7.09 (s, 1H), 7.01–6.99 (m,1H), 2.58–2.56 (m, 1H), 1.91–1.88 (m, 1H), 1.69–1.65 (m, 1H), 1.41–1.39(m, 1H).

MS (M−H)⁺ 195.

Preparation 3 Preparation of 2-(4-chloro-phenyl)-cyclopropanecarboxylicacid

Step A: 3-(4-Chloro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 4-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g), DMAP (12.2g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂ (300 mL) wasstirred at room temperature for 16 h. The reaction was quenched withwater, and the organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrated was evaporated in vacuo, and the crude productwas purified by silica gel flash chromatography eluting with 33% hexanesin ethyl acetate gave the title compound (19.5 g) as a solid.

Step B: 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(4-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (13 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J=6.66, 2H), 7.06 (d, J=6.66 Hz, 2H),3.68 (s, 3H), 3.23 (s, 3H). 2.48–2.38 (m, 2H), 1.65–1.60 (m, 1H),1.29–1.23 (m, 1H).

MS (M+H)⁺ 240.

Step C: Preparation of 2-(4-chloro-phenyl)-cyclopropanecarboxylic acid

A mixture of 2-(4-chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.3 g).

¹H NMR (300 MHz, CDCl₃) δ 7.27 (d, J=10 Hz, 2H), 7.05 (d, J=10 Hz, 2H),2.58–2.56 (m, 1H), 1.87–1.85 (m, 1H), 1.68–1.65 (m, 1H), 1.39–1.36 (m,1H),

MS (M−H)⁺ 195.

Preparation 4 Preparation of 2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid

Step A: 3-(2-Fluoro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 2-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g), DMAP (12.2g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂ (300 mL) wasstirred at room temperature for 16 h. The reaction was quenched withwater, and the organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrated was evaporated in vacuo, and the crude productwas purified by silica gel flash chromatography eluting with 33% hexanesin ethyl acetate gave the title compound (20 g) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=16.0 Hz, 1H), 7.56–7.53 (m, 1H),7.34–7.31 (m, 1H), 7.17–7.05 (m, 2H), 3.76 (s, 3H), 3.31 (s, 3H).

MS (M+H)⁺ 210.

Step B: 2-(2-Fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(2-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (16 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.13–7.08 (m, 1H), 7.01–6.92 (m, 2H), 3.66 (s,3H), 3.19 (s, 3H). 2.58–2.54 (m, 1H), 2.40–2.35 (m, 1H), 1.60–1.54 (m,1H), 1.32–1.25 (m, 1H).

MS (M+H)⁺ 224.

Step C: Preparation of 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid

A mixture of 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (8.92 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7 g).

¹H NMR (300 MHz, CDCl₃) δ 7.26–7.18 (m, 1H), 7.08–6.95 (m, 2H),2.75–2.71 (m, 1H), 1.95–1.91 (m, 1H), 1.70–1.63 (m, 1H), 1.49–1.43 (m,1H).

Preparation 5 Preparation of 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid

Step A: 3-(3-Fluoro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 3-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g), DMAP (12.2g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂ (300 mL) wasstirred at room temperature for 16 h. The reaction was quenched withwater, and the organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrated was evaporated in vacuo, and the crude productwas purified by silica gel flash chromatography eluting with 33% hexanesin ethyl acetate gave the title compound (20.2 g) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, J=15.81 Hz, 1H), 7.36–7.23 (m, 3H),7.08–6.99 (m, 2H), 3.77 (s, 3H), 3.31 (s, 3H).

MS (M+H)⁺ 210.

Step B: 2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(3-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (18 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.25–7.18 (m, 1H), 6.93–6.78 (m, 2H), 3.69 (s,3H), 3.23 (s, 3H). 2.53–2.44 (m, 2H), 1.67–1.60 (m, 1H), 1.30–1.25 (m,1H). MS (M+H)⁺ 224.

Step C: Preparation of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid

A mixture of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (8.96 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.1 g).

¹H NMR (300 MHz, CDCl₃) δ 7.28–7.21 (m, 1H), 7.94–6.88 (m, 2H),6.81–6.76 (m, 1H), 2.60–2.57 (m, 1H), 1.92–1.87 (m, 1H), 1.71–1.66 (m,1H), 1.42–1.37 (m, 1H).

MS (M−H)⁺ 179.

Preparation 6 Preparation of 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid

Step A: 3-(4-Fluoro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 4-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g), DMAP (12.2g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂ (300 mL) wasstirred at room temperature for 16 h. The reaction was quenched withwater, and the organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrated was evaporated in vacuo, and the crude productwas purified by silica gel flash chromatography eluting with 33% hexanesin ethyl acetate gave the title compound (20.5 g) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, J=15.71 Hz, 1H), 7.56–7.53 (m, 2H),7.08–7.03 (m, 1H), 6.92 (d, J=15.71 Hz, 1H), 3.75 (s, 3H), 3.30 (s, 3H).

MS (M+H)⁺ 210.

Step B: 2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(4-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20.4 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (15 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.11–6.93 (m, 4H), 3.69 (s, 3H), 3.23 (s, 3H).2.53–2.44 (m, 2H), 1.64–1.57 (m, 1H), 1.27–1.25 (m, 1H).

MS (M+H)⁺ 224.

Step C: Preparation of 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid

A mixture of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (8.96 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.1 g).

¹H NMR (300 MHz, CDCl₃) δ 7.10–6.94 (m, 4H), 2.60–2.57 (m, 1H),1.87–1.82 (m, 1H), 1.69–1.64 (m, 1H), 1.40–1.35 (m, 1H).

Preparation 7 Preparation of2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid

Step A: 3-(2,5Difluoro-phenyl)-N-methoxy-N-methyl-acrylamide

A mixture of 2,5-difluorocinnamic acid (18.4 g), EDAC.HCl (23 g), DMAP(12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂ (300mL) was stirred at room temperature for 16 h. The reaction was quenchedwith water, and the organic layer was washed with brine, dried overMgSO₄ and filtered. The filtrated was evaporated in vacuo, and the crudeproduct was purified by silica gel flash chromatography eluting with 33%hexanes in ethyl acetate gave the title compound (22.1 g) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=15.96 Hz, 1H), 7.27–7.22 (m, 1H),7.05–6.99 (m, 3H), 3.79 (s, 3H), 3.30 (s, 3H).

MS (M+H)⁺ 228.

Step B: 2-(2,5difluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(2,5-difluoro-phenyl)-N-methoxy-N-methyl-acrylamide (21 g) was addedto the above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (18 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 6.96–6.93 (m, 1H), 6.86–6.82 (m, 1H),6.72–6.67 (m, 1H), 3.71 (s, 3H), 3.24 (s, 3H). 2.69–2.60 (m, 1H),2.38–2.42 (m, 1H), 1.670–1.60 (m, 1H), 1.1.31–1.26 (m, 1H).

MS (M+H)⁺ 242.

Step C: Preparation of 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid

A mixture of 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.8 g).

¹H NMR (300 MHz, CDCl₃) δ 7.02–6.86 (m, 2H), 6.68–6.62 (m, 1H),2.74–2.68 (m, 1H), 1.94–1.89 (m, 1H), 1.71–1.67 (m, 1H), 1.44–1.39 (m,1H).

Preparation 8 Preparation of{1-[3-(1-Amino-ethyl)-phenyl]-pyrrolidin-3-yl}-dimethyl-amine

Step A: [(S)-1-(3-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester

To a solution of (S)-1-(3-bromo-phenyl)-ethylamine (8 g, 40 mmol) andEt₃N (8.4 mL, 60 mmol) in CH₂Cl₂ (200 mL) was added di-tert-butyldicarbonate (8.7 g, 40 mmol), and the reaction mixture was stirred atroom temperature for 4 h. HCl 0.25 N (100 mL) was added and the twolayers were separated. The organic layer was dried over anhydrousmagnesium sulfate and filtered, and the filtrate was concentrated invacuo to provide the title compound (12 g) as a white solid.

¹H NMR (CDCl₃, 400 MHz): δ 1.42 (m, 12H), 4.76 (m, 3H), 7.1–7.3 (m, 2H),7.36 (d, J=7.1 Hz, 1H). 7.46 (s, 1H).

Step B: {1-[3-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-carbamicacid tert-butyl ester

A mixture of (S )[1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butylester (6 g), (3R)-3-(dimethylamino)-pyrrolidine (4.56 g), Pd₂(dba)₃(1.83 g), di-t-butyl-biphenylphosphine (600 mg), K₃PO₄ (8.48 g) in DME(40 mL) was stirred at reflux for 16 h. The reaction mixture was cooleddown to room temperature, diluted with methylene chloride, and filtered.The filtrated was evaporated in vacuo, and the crude product waspurified by Flash Chromatography using Biotage eluting with 20% MeOH inethyl acetate to give the title compound (1.8 g) as an oil.

MS (M+H)⁺ 334.

Step C: 1-[3-(1-Amino-ethyl)-phenyl]-pyrrolidin-3-yl}-dimethyl-amine

A mixture of{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (1.8 g) and 4 ml of 4 N HCl in ethyl acetate (10 mL) at50° C. was stirred for 2 h. After concentration, the residue wasneutralized with 10 N NaOH and extracted with methylene chloride. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedto give the crude product (1.25 g) as an oil.

MS (M+H)⁺ 234.

Preparation 9 Preparation of(R)-2-Amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol

Step A: 2-Bromo-1-fluoro-4-vinyl-benzene

To a suspension of Ph₃PCH₃Br (57 g) in THF (240 mL) at 0° C. wasdropwise added n-BuLi (1.6 N, 100 mL). The resulting mixture was allowedto warm to room temperature and stirred for 1 h. After recooling to 0°C., a solution of 3-bromo-4-fluoro-benzaldehyde (20.3 g) in THF (20 mL)was added. The resulting mixture was allowed to warm to room temperatureand stirred for 1 h. The reaction mixture was quenched with water,concentrated, and extracted with methylene chloride. The combinedorganic layers were dried over magnesium sulfate, concentrated undervacuum. The crude product was purified by flash chromatography elutingwith 10% ethyl acetate in hexanes to give the title compound as an oil(18 g).

¹H NMR (CDCl₃): δ 7.59–7.56 (m, 1H), 7.31–7.27 (m, 1H), 7.05 (t, J=8.4Hz, 1H), 6.65 (dd, J=17.7, 11.1 Hz, 1H), 6.55 (d, J=17.4 Hz, 1H), 5.28(d, J=10.8 Hz, 1H).

Step B: 4-(2-Fluoro-5-vinyl-phenyl)-morpholine

A mixture of 2-bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine (20 mL),Pd₂(dba)₂ (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K₃PO₄ (17 g)in DME (60 mL) was stirred at reflux for 4 h. The reaction mixture wascooled down to room temperature, diluted with methylene chloride, andfiltered. The filtrate was concentrated in vacuo. The crude product waspurified by Flash Chromatography of Biotage eluting with 7% ethylacetate in hexanes to give the title compound as an oil (5 g).

¹H NMR (CDCl₃): δ 7.24–6.93 (m, 3H), 6.68 (dd, J=17.7, 10.8 Hz, 1H),5.66 (d, J=17.4 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H). 3.88 (m, 4H), 3.10 (m,4H).

MS (M+H)⁺ 208.

Step C: (R )-4-of[1-(Fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acidtert-butyl ester

Sodium hydroxide (3.6 g) was dissolved in water (220 mL). 10 mL of thissolution was used to dissolve potassium osmium (VI) oxide dihydrate (434mg) to get a purple suspension. The rest of the sodium hydroxidesolution was treated with t-butyl carbamate (10.666 g) in n-propanol(120 mL), followed by addition of t-butyl hypochlorite (11 mL). Thissolution was stirred for 5 min, then (DHQD)₂PHAL (1466 mg) in n-propanol(120 mL) was added, followed by a solution of4-(2-Fluoro-5-vinyl-phenyl)-morpholine (5 g) in n-propanol (206 mL) anda solution of potassium osmium (VI) oxide dihydrate previously made. Thereaction mixture was stirred at room temperature for 0.5 h. The reactionmixture was quenched with saturated Na₂SO₃ solution. Afterconcentration, the residue was extracted with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate, concentratedunder vacuum. The crude product was purified by flash chromatographyeluting with 33% ethyl acetate in hexanes to give the title compound asa solid (2.2 g).

¹H NMR (CDCl₃): δ 7.03–6.83 (m,3H), 5.19 (br s, 1HO, 4.68 (br s, 1H),3.87 (m, 6H), 3.09 (m, 4H), 1.44 (s, 9H).

MS (M+H)⁺ 341.

Step D: (R)-2-Amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol

A solution of TFA (5 mL) and (R)-[1-(fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acidtert-butyl ester(1.2 g) in methylene chloride (15 mL) was stirred for 2h. After concentration, the residue was neutralized with 10 N NaOH andextracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give the titlecompound as a solid (720 mg).

¹H NMR (CDCl₃): δ 7.07–6.87 (m, 3H), 4.04–4.00 (m, 1H), 3.87–3.84 (m,4H), 3.73–3.68 (m, 1H), 3.55–3.52 (m, 1H), 3.09–3.06 (m, 4H).

MS (M+H)⁺ 241.

Preparation 10 Preparation of (R)-2-Amino-2-naphthalen-2-yl-ethanolhydrochloride

Step A: (R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic acid tert-butylester

Sodium hydroxide (1.89 g, 16 mmol) was dissolved in water (115 mL). 5.4mL of this solution was used to dissolve potassium osmium (VI) oxidedihydrate (240 mg) to get a purple suspension. The rest of the sodiumhydroxide solution was treated with t-butyl carbamate (5.580 g, 47.1mmol) in n-propanol (54 mL), followed by addition of t-butylhypochlorite (5.4 mL, 47.1 mmol). This solution was stirred for 5 min,then (DHQD)₂PHAL (630 mg) in n-propanol (54 mL) was added, followed by asolution of 2-vinylnaphthalene (2.5 g, 16 mmol) in n-propanol (54 mL)and a solution of potassium osmium (VI) oxide dihydrate previously made.The reaction mixture was stirred at room temperature for 0.5 hr. Thereaction mixture was quenched with saturated NaHSO₃ solution. Afterconcentration, the residue was extracted with ethyl acetate. Thecombined organic layer was dried over magnesium sulfate, concentratedunder vacuum. The crude product was purified by flash chromatographywith 20% ethyl acetate in hekanes to give the title compound (2.6 g) asa solid.

¹H NMR (CDCl₃): δ 7.83–7.74 (m, 4H), 7.47–7.37 (m, 3H), 5.39 (br s, 1H),4.91 (br s, 1H), 3.90 (d, J=3.9 Hz, 2H), 1.44 (s, 9H).

MS (M+H)⁺ 288.

Step B: (R)-2-Amino-2-naphthalen-2-yl-ethanol hydrochloride

(R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic acid tert-butyl ester(2.5 g) and 9 mL of 4 N HCl in ethyl acetate at 50° C. was stirred for 2h. After concentration, the residue was neutralized with 10 N NaOH andextracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give the title compound(1.2 g) as a solid which was used in the next step without furtherpurification.

MS (M+H)⁺ 188.

Preparation 11 Preparation of (S)-1-(3-pyridin-3-yl-phenyl)-ethylamine

To a solution of (S)-1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butylester (1.5 g, 5 mmol) and pyridine-3-boronic acid (921 mg, 7.5 mmol) inethyleneglycoldimethylether (25 mL) in a sealed tube were added cesiumcarbonate (3.25 g, 10 mmol) and water (10 mL). Argon was bubbled intothe above mixture for 10 min, and Pd(PPh₃)₄ (289 mg, 0.25 mmol) wasadded. The reaction mixture was stirred at 100° C. for 18 h and cooleddown to room temperature. Ethyl acetate (100 mL) was added, theresulting solution was washed with NH₄Cl (sat.) (2×100 mL), the organiclayer was dried over anhydrous magnesium sulfate, filtered and thefiltrate was concentrated in vacuo. The crude product was diluted inCH₂Cl₂ (30 mL) and trifluoroacetic acid (10 mL). The reaction mixturewas agitated for 1 h and concentrated in vacuo. The residue was purifiedby solid phase extraction (SCX cartridge, silca gel benzene sulfonicacid linked) to give the title product (424 mg) as a yellow oil.

¹H NMR (CDCl₃, 400 MHz): δ 1.26 (d, 3H, J=6.6 Hz), 3.90 (q, 1H, J=6.6Hz), 6.87 (dd, 1H, J=4.8, 7.8 Hz), 7.2–7.35 (m, 3H), 7.45–7.55 (m, 2H),8.64 (s, 1H),9.11 (s, 1H).

Preparation 12 Preparation of(S)-1-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethylamine

Step A: [(S)-1-(phenyl 3-Boronic acid)-ethyl]-carbamic acid tert-butylester

(S)-1-(3-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (5 g, 16.6mmol) were added in THF (100 mL)and cooled to −78° C., methyllithium(11.8 mL, 1.4M in Et₂O, 16.6 mmol) was added, and the reaction mixturewas stirred for 5 min. tert-Butyllithium (19.6 mL, 1.7 M in pentane,33.4 mmol) was added, the reaction mixture was stirred for 5 min, andtrimethylborate (2.82 mL, 24.9 mmol) was added rapidly. The reactionmixture was agitated for 1 h, NH₄Cl (sat.) (100 mL) was added, and theresulting solution was allowed to reach 23° C. The reaction mixture wasextracted with ethyl acetate (3×100 mL), the organic layer was driedover anhydrous magnesium sulfate and filtered, and the filtrate wasconcentrated in vacuo. The crude product was purified by flashchromatography (30% EtOAC/Hex.) to provide the title compound (2.7 g) aswhite solid.

¹H NMR (DMSO d₆, 400 MHz): δ 1.2–1.4 (m, 12H), 4.6–4.7 (m, 3H), 7.2–7.4(m, 2H), 7.6–7.8 (m, 2H).

Step B: (S)-1-[3-(6-chloro-pyridin-3-yl)-phenyl]-ethylamine

To a solution of (S)-1-(phenyl-3-boronic acid)-ethyl]-carbamic acidtert-butyl ester (1.29 g, 4.86 mmol) and 2-chloro-5-Iodo-pyridine (1.4g, 11.4 mmol) in ethyleneglycoldimethylether (25 mL) in a sealed tubewere added cesium carbonate (4.75 g, 14.6 mmol) and water (5 mL). Argonwas bubbled in to the above mixture for 10 min, and Pd(PPh₃)₄ (280 mg,0.24 mmol) was added. The reaction mixture was stirred at 100° C. for 18hand then cooled down to room temperature. Ethyl acetate (100 mL) wasadded, the resulting solution was washed with NH₄Cl (sat.) (2×100 mL),and the organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated in vacuo and the crude productwas diluted in CH₂Cl₂ (30 mL) and trifluoroacetic acid (10 mL). Thereaction mixture was agitated for 1 h and concentrated in vacuo. Theresidue was purified by solid phase extraction (SCX cartridge, silca gelbenzene sulfonic acid linked) to give the title product (785 mg, 69%) asyellow oil.

¹H NMR (DMSO d₆, 400 MHz): δ 1.28 (d, 3H, J=6.8 Hz), 4.04 (q, 1H, J=6.8Hz), 7.4–7.45 (m, 2H), 7.5–7.55 (m, 1H), 7.61 (d, 1H J =7.8 Hz,), 7.72(s, 1H), 8.15 (dd, 1H, J=8.3, 2.5 Hz,), 8.73 (d, 1H, J=3.3 Hz).

Preparation 13 Preparation of(S)-1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethylamine

To a solution of (s)-1-(3-Bromo-phenyl)-ethyl]-carbamic acid tert-butylester (2.3 g, 7.6 mmol) and 2-fluoropyridine-3-boronic acid (1 g, 7.09mmol in ethyleneglycoldimethylether (30 mL) were added cesium carbonate(6.3 g, 19.3 mmol) and water (5 mL. Argon was bubbled into the abovesolution for 10 min, and Pd(PPh₃)₄ (372 mg, 0.32 mmol) was added. Thereaction mixture was stirred at 100° C. for 18 h and then cooled down toroom temperature. Ethyl acetate (100 mL) was added, the resultingsolution was washed with NH₄Cl (sat.) (2×100 mL), and the organic layerwas dried over anhydrous magnesium sulfate and filtered. The filtratewas concentrated in vacuo and the crude product was diluted in CH₂Cl₂(30 mL) and trifluoroacetic acid (10 mL). The reaction mixture wasagitated for 1 h and concentrated in vacuo. The residue was purified bysolid phase extraction (SCX cartridge, silca gel benzene sulfonic acidlinked) to give the title product (1.18 g) as brown oil.

¹H NMR (DMSO d₆, 400 MHz): δ 1.26 (d, 3H, J=6.6 Hz), 4.06 (q, 1H, J=6.6Hz), 7.28 (dd, 1H J=8.6, 3.3 Hz,), 7.4–7.45 (m, 2H), 7.5–7.55 (m, 1H),7.71 (s, 1H), 8.27 (dd, 1H J=8.6, 2.8 Hz,), 8.54 (d, 1H J=2.5 Hz,).

EXAMPLES Example 1 2-(4-chloro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide

A mixture of 1-(2,3-dihydro-benzofuran-5-yl)-ethylamine (0.1 mmol),2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl(0.2 mmol), DMAP (0.2 mmol), and triethylamine (0.4 mmol) indichloromethane (2 mL) was stirred at room temperature overnight. Thereaction mixture was purified by flash chromatography eluting with 50%hexanes in ethyl acetate to give the title compound (23 mg) as a solid.

¹H NMR (CDCl₃): δ 7.24–7.16 (m, 3H), 7.07–6.96 (m, 3H), 6.75–6.71 (m,1H), 5.09–5.04 (m, 1H), 4.59–4.53 (m, 2H), 3.22–3.15 (m, 2H), 2.47–2.43(m, 1H), 1.63–1.46 (m, 5H), 1.19–1.15 (m, 1H).

MS (M+H)⁺ 342.

HPLC rt: 1.46 min (method a)

Examples 2–7

Examples 2–7 were prepared from appropriate acids by the generalprocedure used to prepare Example 1.

HPLC Mass Example rt (min), (M + H)⁺ No. Structure Chemical Name methodm/z 2

2-(2-Chloro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide 1.40 (a) 342 3

2-(2-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide 1.36 (a) 326 4

2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide 1.37 (a) 326 5

2-(4-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide 1.36 (a) 326 6

2-(2,5-Difluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide 1.38 (a) 344 7

2-Phenyl-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide 1.33 (a) 308

Example 8 2-Phenyl-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide

A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol),2-phenyl-cyclopropanecarboxylic acid (0.2 mmol), EDAC.HCl (0.4 mmol),DMAP (0.2 mmol), and triethylamine (0.6 mmol) in dichloromethane (2 mL)was stirred at room temperature for 12 h. The reaction mixture waspurified by flash chromatography eluting with 50% hexanes in ethylacetate to give the desired product (52 mg) as a solid.

¹H NMR (400 Hz, DMSO): δ 8.67–8.65 (m, 1H), 7.88–7.84 (m, 4H), 7.49–7.46(m, 3H), 7.29–7.19 (m, 4H), 5.05–4.92 (m, 2H), 3.67–3.63 (m, 2H),2.18–2.06 (m, 2H), 1.30–1.17 (m, 2H).

MS (M+H)⁺ 332.

HPLC rt: 1.39 min (method a)

Examples 9–15

Examples 9–15 were prepared from appropriate acids by the generalprocedure used to prepare Example 8.

HPLC Mass Example rt (min), (M + H)⁺ No. Structure Chemical Name methodm/z 9

2-(2-Chloro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.45 (a) 366 10

2-(3-Chloro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.53 (a) 366 11

2-(2-Fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.39 (a) 350 12

2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.43 (a) 350 13

2-(4-Fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.40 (a) 350 14

2-(2,5-Difluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.44 (a) 368 15

2-(phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.39 (a) 332

Example 16 2-Phenyl-cyclopropanecarboxylic acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide

A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol(0.1 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl(0.2 mmol), DMAP (0.1 mmol), triethylamine (0.4 mmol) in dichloromethane(2 mL) was stirred at room temperature overnight. The reaction mixturewas purified by flash chromatography with 3% methanol in ethyl acetateto give the desired product (27 mg) as a solid.

¹H NMR (400 Hz, DMSO): δ 8.53–8.47 (m, 1H), 7.28–6.96 (m, 47H),4.86–4.84 (m, 2H), 3.75–3.70 (m, 4H), 53.52–3.50 (m, 2H), 3.00–2.97 (m,4H), 2.25–2.15 (m, 1H), 2.04–2.01 (m, 1H), 1.35–1.17 (m, 2H).

MS (M+H)⁺ 385.

HPLC rt: 1.33 min (method a)

Examples 17–23

Examples 17–23 were prepared from appropriate acids by the generalprocedure used to prepare Example 16.

HPLC Mass Example rt (min), (M + H)⁺ No. Structure Name method m/z 17

2-(2-Chloro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.39,1.44(a) 419 18

2-(3-Chloro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.50,1.55(a) 419 19

2-(4-Chloro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.49,1.54(a) 419 20

2-(2-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.42 (a)403 21

2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.39 (a)403 22

2-(4-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.38 (a)403 23

2-(2,5-Difluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide 1.38 (a)421

Examples 24–31

Examples 24–31 were prepared by the general procedure: A mixture ofappropriate amine (0.1 mmol), appropriate cinnamic acid (0.1 mmol),EDC.HCl (0.2 mmol), DMAP (0.2 mmol), and triethylamine (0.4 mmol) indichloromethane (2 mL) was stirred at room temperature for 12 h. Thereaction mixture was purified by flash chromatography with 50% hexanesin ethyl acetate to give the titled compounds.

HPLC Mass Example rt (min), (M + H)⁺ No. Structure Chemical name methodm/z 24

2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide 1.54 (a) 334 25

2-(4-Fluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide 1.62 (a) 334 26

2-(2,5-Difluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide 1.56 (a) 352 27

2-Phenyl-cyclopropanecarboxylicacid (1-naphthalen-2-yl-ethyl)-amide 1.53(a) 316 28

2-(4-Fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-amide 1.15 (a)396 29

2-(2,5-Difluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-amide 1.10,1.15(a) 413 30

2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide 1.08 (a) 361 31

2-(2,5-Difluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide 1.09 (a) 379

Examples 32–36

Examples 32–36 were prepared by the general procedure: A mixture of theappropriate cinnamic acid (0.083 mmol),(S)-1-(3-pyridin-3-yl-phenyl)-ethylamine (12.7 mg, 0.064 mmol), EDAC(18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol), DMF (2 mL) anddiisopropylethylamine (33 μL, 0.192 mmol) was stirred at 23° C. for 18h. The residue was purified by preparative HPLC (Primeshere C18-HC21.2×100 mm; (5 mM NH₄OAc ) 0–100% gradient over 5 min; 20 mL/min flowrate) to afford the titled products.

HPLC Mass Example rt (min), (M + H)⁺ No. Structure Chemical name methodm/z 32

(S)-2-Phenyl-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide 1.75 (b) 343 33

(S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide 1.95 (b) 379 34

(S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(6-chloro-pyridin-3-yl)-phenyl]-ethyl}-amide 2.00 (b) 395 35

(S)-2-Phenyl-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide 1.87 (c) 361 36

(S)-2-(2-Fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide 1.91 (c) 379

1. A compound of Formula I or a pharmaceutically acceptable salt thereof

wherein R is C₁₋₄ alkyl, CF₃ or hydroxymethyl; R¹ and R² are eachindependently hydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ isselected from the group consisting of optionally substitutedmorpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, inwhich said substituent is independently selected from the groupconsisting of C₁₋₄alkyl, dimethylamino, hydroxymethyl, chloro andfluoro; R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together are—CH═CH—CH═CH— or —CH₂CH₂O—; and R³, R⁶ and R⁷ are each independentlyselected from hydrogen or fluoro.
 2. The compound of claim 1 having theFormula Ic or a pharmaceuticallyacceptable salt thereof

wherein R is methyl or hydroxymethyl; R¹ and R² are each independentlyhydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ is selected from thegroup consisting of optionally substituted morpholin-4-yl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent isindependently selected from the group consisting of C₁₋₄alkyl,dimethylamino, hydroxymethyl, chloro and fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; andR³, R⁶ and R⁷ are each independently selected from hydrogen or fluoro.3. The compound of claim 1 selected from the group consisting of:2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyll}-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;(S)-2-phenyl-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;(S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide;(S)-2-phenyl-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; and(S)-2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of claim 1 in association with a pharmaceutically acceptablecarrier, adjuvant or diluent.
 5. A method for the treatment of disordersresponsive to opening of the KCNQ potassium channels in a mammal in needthereof wherein said disorders are acute and chronic pain, migraine,neuropathic pain, bipolar disorders, convulsions, mania, epilepsy,anxiety and depression, which comprises administering to said mammal atherapeutivally effective amount of the compound of claim
 1. 6. Themethod of claim 5 wherein said disorder is migraine.
 7. The method ofclaim 5 wherein said disorder is neuropathic pain.